Managing Injuries of the Neck Trial (MINT) : design of a randomised controlled trial of treatments for whiplash associated disorders

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised

KIAA0101 Is Overexpressed, and Promotes Growth and Invasion in Adrenal Cancer

Background: KIAA0101 is a proliferating cell nuclear antigen-associated factor that is overexpressed in some human malignancies. Adrenocortical neoplasm is one of the most common human neoplasms for which the molecular causes are poorly understood. Moreover, it is difficult to distinguish between localized benign and malignant adrenocortical tumors. For these reasons, we studied the expression, function and possible mechanism of dysregulation of KIAA0101 in human adrenocortical neoplasm. Methodology/Principal Findings: KIAA0101 mRNA and protein expression levels were determined in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 adrenocortical carcinoma (ACC). SiRNA knockdown was used to determine the functional role of KIAA0101 on cell proliferation, cell cycle, apoptosis, soft agar anchorage independent growth and invasion in the ACC cell line, NCI-H295R. In addition, we explored the mechanism of KIAA0101 dysregulation by examining the mutational status. KIAA0101 mRNA (9.7 fold) and protein expression were significantly higher in ACC (p,0.0001). KIAA0101 had sparse protein expression in only a few normal adrenal cortex samples, which was confined to adrenocortical progenitor cells. KIAA0101 expression levels were 84 % accurate for distinguishing between ACC and normal and benign adrenocortical tumor samples. Knockdown of KIAA0101 gene expression significantly decreased anchorage independent growth by 80 % and invasion by 60 % (p = 0.001; p = 0.006). W

Analyses of associations between three positionally cloned asthma candidate genes and asthma or asthma-related phenotypes in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Six asthma candidate genes, ADAM33, NPSR1, PHF11, DPP10, HLA-G, and CYFIP2, located at different chromosome regions have been positionally cloned following the reported linkage studies. For ADAM33, NPSR1, and CYFIP2, the associations with asthma or asthma-related phenotypes have been studied in East Asian populations such as Chinese and Japanese. However, for PHF11, DPP10, and HLA-G, none of the association studies have been conducted in Asian populations. Therefore, the aim of the present study is to test the associations between these three positionally cloned genes and asthma or asthma-related phenotypes in a Chinese population.</p> <p>Methods</p> <p>Two, five, and two single nucleotide polymorphisms (SNPs) in the identified top regions of PHF11, DPP10, and HLA-G, respectively, were genotyped in 1183 independent samples. The study samples were selected based on asthma affectation status and extreme values in at least one of the following three asthma-related phenotypes: total serum immunoglobulin E levels, bronchial responsiveness test, and skin prick test. Both single SNP and haplotype analyses were performed.</p> <p>Results</p> <p>We found that DPP10 was significantly associated with bronchial hyperresponsiveness (BHR) and BHR asthma after the adjustment for multiple testing; while the associations of PHF11 with positive skin reactions to antigens and the associations of HLA-G with BHR asthma were only nominally significant.</p> <p>Conclusion</p> <p>Our study is the first one to provide additional evidence that supports the roles of DPP10 in influencing asthma or BHR in a Chinese population.</p

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-β2 (TGF-β2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-β2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-β2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-β2 and inhibited by TGF-β2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-β domain of versican was able to reverse the effect of TGF-β2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-β2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1

The (cost-)effectiveness of a lifestyle physical activity intervention in addition to a work style intervention on the recovery from neck and upper limb symptoms in computer workers

BACKGROUND: Neck and upper limb symptoms are frequently reported by computer workers. Work style interventions are most commonly used to reduce work-related neck and upper limb symptoms but lifestyle physical activity interventions are becoming more popular to enhance workers health and reduce work-related symptoms. A combined approach targeting work style and lifestyle physical activity seems promising, but little is known on the effectiveness of such combined interventions. METHODS/DESIGN: The RSI@Work study is a randomised controlled trial that aims to assess the added value of a lifestyle physical activity intervention in addition to a work style intervention to reduce neck and upper limb symptoms in computer workers. Computer workers from seven Dutch companies with frequent or long-term neck and upper limb symptoms in the preceding six months and/or the last two weeks are randomised into three groups: (1) work style group, (2) work style and physical activity group, or (3) control group. The work style intervention consists of six group meetings in a six month period that take place at the workplace, during work time, and under the supervision of a specially trained counsellor. The goal of this intervention is to stimulate workplace adjustment and to improve body posture, the number and quality of breaks and coping behaviour with regard to high work demands. In the combined (work style and physical activity) intervention the additional goal is to increase moderate to heavy physical activity. The control group receives usual care. Primary outcome measures are degree of recovery, pain intensity, disability, number of days with neck and upper limb symptoms, and number of months without neck and upper limb symptoms. Outcome measures will be assessed at baseline and six and 12 months after randomisation. Cost-effectiveness of the group meetings will be assessed using an employer's perspective. DISCUSSION: This study will be one of the first to assess the added value of a lifestyle physical activity intervention in addition to a work style intervention in reducing neck and upper limb symptoms of computer workers. The results of the study are expected in 2007

Increasing genome instability in adrenocortical carcinoma progression with involvement of chromosomes 3, 9 and X at the adenoma stage

The investigation of chromosomal aberrations in adrenocortical tumours has been limited by the difficulties of applying classical cytogenetics to tumours with low levels of proliferation. We have therefore applied the technique of interphase cytogenetics to paraffin-embedded archival specimens of 14 adrenocortical adenomas and 13 carcinomas. Hybridizations were performed using centromere-specific probes to chromosomes 3, 4, 9, 17, 18 and X, which have been shown to be altered in other types of tumours. Chromosomal imbalance was defined on the basis of changes in both chromosome index (CI) and signal distribution (SD). Where only one of these was altered, this was classified as a tendency to gain or loss. On the basis of the analysis of optimal hybridizations, carcinomas showed gains in all chromosomes studied, five of nine showing gains in multiple chromosomes. Gains were most common in chromosomes 3, 9 and, in particular X, eight of 11 showing gain, and one a tendency to gain. Chromosomal gain was seen less commonly in adenomas, but again chromosomes 3, 9 and X were involved. Losses were infrequent, only one carcinoma showing loss of chromosome 18, and adenomas showing a tendency to loss of chromosomes 4 (two cases), 17 (one case) and 18 (two cases). Our data suggest that changes in chromosomes 3, 9 and X are early events in adrenocortical tumorigenesis, and that there is increasing chromosomal instability with tumour progression. © 1999 Cancer Research Campaig

Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.

Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET

Integrative Genome Comparison of Primary and Metastatic Melanomas

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes